Prostate cancer (PCa) can preferentially metastasize to the bone, with bone involvement occurring in 90% of patients with metastatic disease. These metastases can cause severe bone pain, replacement of bone marrow, pathologic fracture, and spinal cord compression (see Bubendorf L, et al. (2000) Hum Pathol 31:578-583 and Nieder C, et al. (2010) BMC Urol 10:23). The evaluation of bone metastases obtained through studies of rapid autopsies have shown that bone turnover can increase in these metastatic sites; however, the new bone can form layers of fragile, woven bone with reduced mechanical strength (see Roudier M P, et al. (2008) J Urol 180:1154-1160; Jin J K, et al. (2011) Int J Cancer 128:2545-2561; and Morrissey C, et al. (2013) J Bone Miner Res 28:333-340). In concert with the heterogeneity of bone formation, there can be a wide spectrum of responses to treatment. A number of therapies have been developed to address osteolytic bone metastases, such as bisphosphonates (e.g., zoledronic acid), and more recently, RANKL inhibitors (e.g., Denosumab) (see Fizazi K, et al. (2011) Lancet 377:813-822; Lee R J, et al. (2011) Bone 48:88-95; Valkenburg K C, et al. (2013) Chin J Cancer 32:380-396; and Sturge J, et al. (2011) Nat Rev Clin Oncol 8:357-368). Additionally, a number of factors have been described as possible targets to treat osteoblastic bone metastases including, but not limited to, ET-1, Wnt signaling proteins, and the TGF-β superfamily, including the BMPs (see Valkenburg K C, et al. (2013) Chin J Cancer 32:380-396; Sturge J, et al. (2011) Nat Rev Clin Oncol 8:357-368; Bagnato A, et al. (2011) Br J Pharmacol 163:220-233; Larson S R, et al. (2013) Prostate 73:932-940; and Feeley B T, et al. (2005) J Bone Miner Res 20:2189-2199). While these proteins can promote bone formation in vitro, the specific mechanisms that promote bone growth in PCa patients are largely unknown. Therefore, there has been focus on targeting soluble proteins secreted from tumor cells that promote bone growth within the bone-tumor microenvironment.
One of the major proteins secreted by normal prostatic epithelium and PCa tumor cells is prostatic acid phosphatase (PAP). In 1936, Gutman, et al. described an increase of phosphatase activity at osteoblastic skeletal metastatic sites, indicating that the production of phosphatases may play an important role in dictating the osteoblastic behavior of bone metastasis (see Gutman E B, et al. (1936) Am J Cancer 28:485-495). It was subsequently described that PAP, when added to cell culture, can stimulate collagen synthesis and alkaline phosphatase production in osteoprogenitor cells and osteoblasts. This led to the hypothesis that PAP may directly stimulate bone forming cells, likely contributing to the sclerotic pattern at sites of PCa bone metastases (see Ishibe M, et al. (1991) J Clin Endocrinol Metab 73:785-792). More recently, it was shown that secreted PAP can be expressed in clinical osteosclerotic PCa bone metastases themselves, and that PAP may play a causal role in the osteoblastic nature of PCa bone metastases (see Kirschenbaum A, et al. (2011) Ann N Y Acad Sci 1237:64-70).